Our laboratory has been involved in uncovering the mechanisms by which hepatitis viruses, particularly hepatitis C virus, persist in the liver and cause liver damage. Our projects will advance care of patients with liver diseases through enhanced understanding of what causes chronic viral infection, and will help to identify novel drugs to help treat patients who have been nonresponders or ineligible to receive current treatments.nonresponders or ineligible to receive current treatments.

Raymond Chung, MD, Director of Hepatology and Vice Chief of Gastroenterology, leads an NIH-funded Center for Human Immunology U19 Program, a consortium of 8 projects centered on understanding the basis for the persistence of hepatitis C virus, an infection with a remarkable tendency to become chronic.

His laboratory has been committed to uncovering the strategies employed by hepatitis C virus to ensure its persistence in the liver, and the basis by which the infection causes liver scarring and cancer.

These studies include investigations into the basis for host genetic predispositions to successful responses to therapy with interferon. His group has also been exploring the basis for HCV’s disruptive effects on lipid metabolism and insulin handling by the liver that lead to alterations in cholesterol levels and increased risk for diabetes.

Dr. Chung also leads the MGH site of the NIH Hepatitis B Research Network, which is committed to long term study of optimal antiviral treatment strategies to prevent cirrhosis and liver cancer in persons chronically infected with this hepatitis virus.

Our laboratory projects include:

Understanding how and why HIV cooperates with HCV to cause more accelerated and severe liver disease than those persons with HCV alone

Identifying the host cellular proteins that facilitate the replication of HCV and exploiting knowledge of these proteins to design innovative treatments for HCV

Identifying the principal genes and proteins responsible for interferon’s known antiviral effects against HCV Investigation of the mechanisms of HCV-associated insulin resistance

Exploration of the antiviral activity of statins against HCV

A pilot clinical trial of naringenin (a compound found in grapefruit) as a potential antiviral drug against HCV

Genetic studies to identify predispositions to fatty liver disease

Development of biomarkers to identify those persons with more severe, progressive forms of fatty liver

Development of biomarkers and prediction rules to identify persons with acute liver failure who are at highest risk for mortality or need for liver transplantation

Wenyu Lin, PhD

Dahlene Fusco, MD, PhD

Jay Luther, MD

Esperance Schaefer, MD, MPH

Lee Peng, MD, PhD

Shadi Salloum, MD, PhD

Cynthia Brisac, PhD

Jian Hong, MD, PhD

Dr. Soung Joung

Daniel Motola, MD, PhD

Lindsay King, MD

Nadia Alatrakchi, MD, PhD

Jessica Mueller

Anna Lidofsky

Matthew Tung

Our laboratory has been focused on the mechanisms of HCV persistence and pathogenesis.

Hepatitis C virus infects 170 million persons worldwide and is remarkable for its predilection for chronicity. It is also a leading cause of chronic liver disease, liver cancer, and is the leading reason for liver transplantation.

We have focused our efforts in development of model systems supportive of HCV replication, elucidating some of the many mechanisms by which viral proteins subvert innate antiviral immunity, particularly type I IFN signaling. We have focused on the actions of HCV core protein, which induces the selective degradation and inhbition of STAT1 phosphorylation.

We are also studying suppressors of cytokine signaling (particularly SOCS3) and their interaction with IFN signaling in chronic HCV.

Identification of the mechanisms underlying control of HCV by interferon alfa and IL28B

Interferon alfa, a type I IFN, exerts its broad antiviral effect through the induction of hundreds of host interferon stimulated genes (ISGs). However, the key genes operative against HCV are unknown.

We have been using functional genomic approaches to elucidate the key genes responsible for type I IFN action, in the hopes of refining treatments that retain interferon’s potency without producing the numerous systemic adverse effects that limit interferon therapy.

In separate studies, a genome wide association study (GWAS) has identified that a polymorphism in the IL28B (IFN lambda-3) locus that is a powerful predictor of success with interferon alfa therapy. We are now exploring the functional basis for this finding using HCV infection models. By identifying the host mediators of IL28B action, we hope to further optimize treatment approaches to HCV.

High throughput screening approaches to the identification of key cellular regulators of HCV replication and persistence

Another avenue our laboratory has taken is a high throughput screen for small molecules that regulate HCV infection using a tractable replicon model.

To accomplish this, we have successfully employed two large scale screening strategies. Using a compound screening library, we have identified a number of small molecules that inhibit HCV replication and have successfully performed target identification to clarify their host cell targets.

Similarly, we have used a whole genome siRNA library approach and identified several dozen host genes that participate in HCV replication. These include proteins involved in the secretory pathway and facilitation of intracellular lipid transport. We believe that these approaches will add to our understanding of the underpinnings of HCV replication and lead to novel strategies to interrupt its lifecycle.

Unraveling the mechanisms underlying the acceleration of HCV pathogenesis by HIV coinfection

We have also been interested in understanding the basis for the observation of more progressive HCV-related liver disease in HIV-infected persons, despite the lack of liver tropism for HIV. We have found that HIV and its envelope protein gp120 can upregulate HCV replication through chemokine receptor-dependent means, and that this upregulation of HCV replication is TGF-b mediated.

This finding may help to explain both the increased levels of HCV replication observed in HIV, but also the acceleration of hepatic fibrosis observed in coinfection.

We are currently studying the mechanisms by which viral proteins induce TGF-beta and, in turn, contribute to hepatic fibrosis. We have also found that HIV can promote hepatocyte apoptosis, highlighting another avenue for its contribution to accelerated pathogenesis.